Novel {66 {hu 9,11{b -Gonadiene-5{60 -ols

ABSTRACT

Novel Delta 9,11-gonadiene-5 Alpha -ols of the formula   WHEREIN R is alkyl of 1 to 4 carbon atoms, K is a blocked ketone in the form of a ketal, thioketal or methyloxime, preferably a ketal, and X is the rest of a pentagonal ring optionally substituted and their preparation which are useful intermediates for the preparation of Delta 4,9,11-gonatrienes.

United States Patent 1 [111 3,872,092 Teutsch Mar. 18, 1975 NOVEL A "-GONADIENE-5a-OLS [57] ABSTRACT [75] Inventor: izgf iz iii Le Novel A "-gonadiene-5a-ols of the formula [73] Assignee: Roussel Uclaf, Paris. France R 22 Filed: Jan. 15, 1974 [2]] App]. No.: 433,569

[30] Foreign Application Priority Data I Jan. 29, 1973 France r. 73.2991 K t [52} U.S. Cl. 260/239.55 C, 260/239.55 R 0H [51] Int. Cl. C07c 173/00 S h 'h' S hdSt 'd s [58] Field of [Mac me earc e em! 5 wherein R is alkyl of l to 4 carbon atoms, K is a [56] References Cited blocked ketone in the form of a ketal, thioketal or me- OTHER PU BLICATIONS Dferassi Steroid Reactions, p. 241, (1963).

Primary E.\aminerHenry A. French Attorney, Agent, or Firm-Hammond & Littell thyloxime, preferably a ketal, and X is the rest of a pentagonal ring optionally substituted and their preparation which are useful intermediates for the preparation of A -gonatrienes.

5 Claims, No Drawings 1 NOVEL A9- "-GONADIENE-S a-OLS OBJECTS OF THE INVENTION It is an object of the invention to provide the novel A gonadicne-Sa-ols of formula I it is another object of the invention to provide a novel process for the preparation of the compounds of formula I.

It is a further object of the invention to provide a novel process for the preparation of N- -gonatrienes starting from the compounds of formula I.

These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION The novel A -gonadiene-5a-ols of the invention have the formula wherein R is alkyl of l to 4 carbon atoms, X is the residue of a pentagonal ring optionally substituted and K is a blocked ketone in the form of a member selected from the group consisting of ketal, thioketal and methyloxime,

A preferred group of compounds of formula I are A--gonadiene-5a-ols of the formula R8 Ia wherein R is alkyl of l to 4 carbon atoms, L is a ketal group, R, is selected from the group consisting of OH, alkyloxy of l to 5 carbon atoms, alkenyloxy of 2 to 5 carbon atoms, acyloxy of l to 12 carbon atoms and tetrahydropyranyloxy and R is selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms or R, may be acyl of 2 to 4 carbon atoms with the in its free form or blocked in the form of a ketal and R is selected from the group consisting of hydrogen, OH and acyloxy or R, and R form a ketalized ketone.

Preferably R is methyl, ethyl, propyl or isopropyl. R, may be alkoxy of l to carbon atoms such as methoxy, ethoxy, propoxy; isopropoxy, etc or alkenyloxy of 2 to 5 carbon atoms such as butenyloxy or isobutenyloxy.

Examples of suitable acids of l to 12 carbon atoms for R, as acyloxy are saturated or unsaturated aliphatic or cycloaliphatic carboxylic acids such as alkanoic acids such as formic acid, acetic acide, propionic acid, butyric acid, isobutyric acid or undecylic acid; cycloalkyl carboxylic acids or cycloalkylalkanoic acids such as cyclopropylcarboxylie acid, eyclopentylcarboxylic acid. cyclohexylearboxylie acid, cyclt'ipcntylacctic acid, cyclopentylpropionic acid, cyclohcxylacctic acid or cyclohcxylpropionic acid; bcnzoic acid or phenylalkanoic acids such as phenylacetic acid or phenylpropionic acid; or amino acids such as diethylaminoacetic acid or aspartic acid.

R 2 may be alkyl such as methyl, ethyl, propyl or isopropyl; alkenyl such as vinyl, allyl, 2'-methyl allyl or isobutenyl; or alkynyl such as ethynyl, l propynyl, 2- propynyl, Z-butynyl or butadiynyl.

The invention is particularly concerned with A gonadiene-Sa-ols in which the ketal in the 3-position and, as the case may be, the ketal in the 17- and 20positions are OY Z groups wherein Y and Z are alkyl of l to 4 carbon atoms or together form an alkylcnc of 2 to 4 carbon atoms. Two specific compounds are 3,20-bis- (ethylenedioxy)- l 9-nor-Apregnadienc-Sa, l 7a-diol and 3-(ethylenedioxy)-A"estradiene-Sa, l7B-diol.

The novel process of the invention for the preparation of compounds of formula 1 comprises reacting a compound of the formula wherein K, R and X have the above definitions with a strong base in an aprotic dipolar solvent to obtain the corresponding compound of formula I.

For the preparation of a compound of formula la, a compound of the formula The compounds of formula 11 are known and can be made by known methods. For example, French Pat. No. 1,550,974 teaches reacting a 13B-alkyl-A gonadiene with an epoxidation agent such as peracetic acid, perphthalic acid or m-chloroperbenzoic acid. The products can also be prepared by reacting a A- gonadiene compound with the 3-ketone blocked in the form of a ketal with the hydroperoxide of hexafluoroacetone to obtain the corresponding 3-ketal-5a, 10aepoxy-A -gonene.

The compounds of formula 1 may be used to prepare A' '-gonatrienes which is also a part of the invention by reacting a compound of formula 1 with an acid agent in an aqueous media to obtain a compound of the formula III wherein R and X have the above definitions.

The compounds of formula la can be reacted with an acid agent in an aqueous media to obtain a compound of the formula wherein R, R, and R have the above definitions.

The acid agent is preferably a sulfonic acid resin or a carboxylic acid resin in the acid form but may be a mineral acid in aqueous media such as hydrochloric acid, sulfuric acid or perchloric acid or a carboxylic acid such as acetic acid, formic acid, citric acid or trichloroacetic acid or mixtures of these acids. Also useful are alkyl sulfonic acids such as methane sulfonic acid or ethane sulfonic acid or arylsulfonic acids such as p-toluenesulfonic acid.

The compounds of formula 1 are produced in good yields from the compounds of formula 11 and they permits direct preparation of the corresponding 13B-alkyl- N' -gonatrienes in excellent yields.

The compounds of formula 1 have a certain industrial interest since the l3B-alkyl-N' -gonatrienes of formula 111 have been described in numerous publications as having very interesting pharmacological properties, notably anabolisant and androgenic activity, estrogenic, progestomimetic and hypophysial inhibiting activity making them useful in human and animal medicines. Some of the publications c. Velluz, C. R. Acad. Sci., 264 C, 1396 (1967); Feyel-Cabannes, Ann. Endocrinol., Vol. 26 (1965), p. 95; and Tremolieres et al, Bull. Acad. Nat. Med.,Vo1. 149 (1965), p. 14.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE 1 3 ,20-bis-(ethylenedioxy )-1 9-nor-A -pregnadiene-5a, l7a-diol STEP A: 3 ,ZO-bis-(ethylenedioxy 1 9nor-A'' -pregnadiene-l 701-01 3.49 g of 3,3-ethy1enedioxy-l9-nor-A pregnadiene-l7a-ol-20-one [prepared by method of Canadian Pat. No. 801,724] were added to a solution of 35 ml of methylene chloride, 35 ml of glycol and 17.5 ml of ethyl orthoformate and 260 mg of p-toluene sulfonic acid were added thereto. After 2 hours of reac tion at 2025C, the solution was neutralized with an excess of sodium bicarbonate and the methylene chlo- 'ride and ethyl orthoformate were evaporated under reduced pressure. The reaction mixture was poured into iced water and held for 2 hours under a nitrogen atmosphere. The mixture was vacuum filtered and the recovered precipitate was washed with water and dried at 50C under reduced pressure to obtain 3.868 g of 3,20- bis-(ethylenedioxy)-l9-nor-A -pregnadiene- 1701-01 melting at 173C.

Analysis: C 1-1 O molecular weight 402.51:

Calculated: %C 71.61; %H 8.51.

STEP B: 3 ,20-bis-(ethylenedioxy)-5a,10a-epoxy-19-nor-A pregnene-l 701-01 43.8 g of 3,20'bis-(ethylenedioxy)-l9-nor-A pregnadiene-l7a-ol were dissolved in a solution of 876 ml of chloroform and 2.4 ml of pyridine and after cooling the solution to 0C, 145 m1 of a solution of 1.13 M of hydroperoxide of hexafluoroacetone in methylene chloride were added thereto. The solution was poured into 500 m1 of 0.1 M sodium thiosulfate and the mixture was extracted with chloroform. The extracts were washed with water and then brought to dryness. The resulting resin was dissolved in a M mixture of methanol-isopropyl ether and the crystals separating were recovered by filtration to obtain 17.52 g of 3,20-bis-(ethylenedioxy)-5oz, IOa-epoxy- 19-nor-A -pregnene-l7a-ol melting at 206C.

Analysis:

Calculated: %C 68.87; %H 8.19. Found: %C 68.6; %H 7.9.

STEP C: 3 ,20-bis-(ethylenedioxy)-19nor-A "-pregnadiene- 5a,] 7a-diol 350 mg of potassium tert.-butylate were added to a solution of 209 mg of 3,20-bis-(ethylenedioxy)-5a,

10a-epoxy-l9-nor-A -pregnene-1701-01 in 2.5 m1 of tetrahydrofuran and the mixture was refluxed for 45 -minutes and then cooled. The reaction mixture was poured over ice and then extracted with methylene chloride. The extracts were evaporated to dryness to obtain 210 mg of 3,20-bis-(ethylenedioxy)-l9-nor- A "-pregnadiene-5a, l7a-diol. 1R Spectrum (chloroform):

OH at 3,566 UV Spectrum (ethanol):

Max. at 245 nm E 608 F 25,500.

EXAMPLE 2 3-ethylenedioxy-A -estradiene-Sa, 17B-diol 350 mg of 80% potassium tert.-butylate were added to a solution of 218 mg of 3-ethylenedioxy-5a, 10aepoxy-l7B-benzoyloxy-A "-estrene (prepared as in French Pat. No. 1,550,974) in 2.5 ml of tetrahydrofuran and the mixture was refluxed for 1 Ahours and then cooled. The mixture was poured into water and extracted with methylene chloride. The extracts were dried, filtered and evaporated to dryness to obtain 140 mg of a resin which was chromatographed over silica with a 1-1 benzene-ethyl acetate eluant to obtain 73 mg of 3-ethylenedioxy-A -estradiene-Sa. l7B-diol melt ing at l65l70C.

UV Spectrum (ethanol):

Max at 246 mn:Em,,1% 668:e= 22.200.

EXAMPLE 3 l9-nor-A-"' -pregnatriene-l 7a-ol-3,20-dionc 100 mg of 3,20-bis-(ethylenedioxy)-l9-nor-A"-- pregnadiene-Sa, l7oz-diol were added to a suspension of 2 ml of 95ethanol and 100 mg of a sulfonic acid resin. The mixture was refluxed for 45 minutes and then was cooled to room temperature. The resin was removed by filtration and the filtrate was evaporated to dryness to obtain 93 mg of l9-nor-A -pregnatriene- 17a-ol-3,20-dione which was chromatographed over silica with a 6-4 benzene-ethyl acetate mixture as eluant. 1R Spectrum (chloroform):

OH at 3,6()l'" ZO-one at 1.710 and 1,697"""; 3-one at 1,661 and 1,650"""; and C=C at l,577"'"". UV Spectrum (ethanol):

Max. at 341 nm: E,,.,,, "70 700 e 22.000.

Various modifications of the process and products of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

1 claim:

1. A compound having the formula wherein R is alkyl of 1 to 4 carbon atoms, L is a ketal group, R, is selected from the group consisting of OH, alkoxy of l to 5 carbon atoms, alkenyloxy of 2 to 5 carbon atoms, acyloxy of an organic carboxylic acid of l to 12 carbon atoms and tetrahydropyranyloxy and R is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms or R, may be acyl of 2 to 4 carbon atoms with the =0 in its free form or blocked in the form of a ketal and R is selected from the group consisting of hydrogen, OH and acyloxy or R, and R form a ketalized ketone.

2. A compound of claim 1 wherein the ketal in the 3-position and in the 17- and 20-positions are groups wherein Z and Y are alkyl of l to 4 carbon atoms or taken together are alkylene of 2 to 4 carbon atoms.

3 A compound of claim 1 which is 3,20-bis- (ethy1enedioxy)- 1-9-nor-A -pregnadiene-z, 17adiol.

4. A compound of claim 1 which is 3-ethylenedioxy- A"'-estradiene-5a, 17B-diol.

5. A process for the preparation of a compound of claim 1 comprising reacting reacting a compound of the formula wherein R, R,, R and L have the definitions of claim 3 with a strong base in an aprotic dipolar solvent. 

1. A COMPOUND HAVING THE FORMULA
 2. A compound of claim 1 wherein the ketal in the 3-position and in the 17- and 20-positions are
 3. A compound of claim 1 which is 3,20-bis-(ethylenedioxy)-19-nor- Delta 9,11-pregnadiene-5 Alpha , 17 Alpha -diol.
 4. A compound of claim 1 which is 3-ethylenedioxy- Delta 9,11-estradiene-5 Alpha , 17 Beta -diol.
 5. A process for the preparation of a compound of claim 1 comprising reacting reacting a compound of the formula 